Reduced nutrient availability (dietary restriction, abbreviated DR) has been shown to be the most powerful modulator of the aging process in mammals, and it doubles the lifespan of the fruit fly, Drosophila melanogaster. The presence of DR regulation of aging in many different species indicates that at least some of the molecular pathways involved in the response are conserved across species, but, with the possible exception of yeast, specific physiological mechanisms mediating it are unknown. In rodents, DR maintains most physiological processes in an apparently youthful and disease-free state. Therefore, it is likely that an understanding of the genetic and physiological mechanisms by which dietary restriction acts to modify patterns of aging would provide important information about the causes of age-associated disease as well as the process of aging itself. My colleagues and I have discovered that in the fruit fly, Drosophila melanogaster, the aging effects of dietary restriction are assessed quickly and precisely by the response to a "switch" from a normal to a low-calorie environment; when adult Drosophila are switched they experience a dramatic and temporally defined reduction of age-specific death rates. This simple observation has three important implications that are exploited in this proposal: (1) transcriptional and physiological changes that modify patterns of aging are restricted to a known temporal window, which is vital for identifying processes that regulate the DR response, (2) the rapid response to DR is a simple, well-defined, and rapidly assessed phenotype, which is crucial for identifying genes that may be required for the response, and (3) an aging response to DR is assessed in two weeks, which is roughly 3-4 times faster than standard lifetime assays. The primary goal of this proposal is to use our recent discovery of the acute response to dietary restriction in Drosophila to identify genetic and physiological mechanisms involved in slowed aging in reduced-calorie environments. We will test several specific candidate genes and pathways that were identified by preliminary microarray analysis.